Heterocyclic agents

ABSTRACT

The invention concerns a 1,2-dihydro-3H-indazol-3-one derivative of formula I ##STR1## wherein Ra is hydrogen, halogeno, hydroxy, cyano, trifluoromethyl, 1-6C)alkyl or (1-6C)alkoxy; 
     Rb is hydrogen or (1-6C)alkyl; 
     Rc is hydrogen, (1-8C)alkyl or (3-8C)alkenyl; and 
     Y is (1-8C)alkyl, (3-8C)alkenyl or (3-8C)alkynyl, or Y is a group of the formula --A--Q in which A is (1-6C)alkylene or (3-6C)alkenylene, and Q is phenyl, naphthyl, pyridyl, thienyl, isoxazolyl, thiazolyl or thiadiazolyl, which may optionally bear one or two substituents; 
     or a pharmaceutically-acceptable salt thereof; 
     or a (12-4C)alkoxycarbonyl derivative thereof. 
     The invention also concerns processes for the manufacture of an indazol-3-one of the formula I and pharmaceutical compositions containing said indazol-3-one. Also included in the invention is a method of treating various inflammatory or allergic diseases using an indazol-3-one of the formula I and the use of such a compound in the production of a new medicament for such use.

This invention concerns novel heterocyclic agents and more particularlynovel indazolone derivatives which are inhibitors of the enzyme5lipoxygenase (hereinafter referred to as 5-LO). The invention alsoconcerns processes for the manufacture of said indazolone derivativesand novel pharmaceutical compositions containing said indazolonederivatives. Also included in the invention is the use of saidindazolone derivatives in the treatment of various inflammatory and/orallergic diseases in which the direct or indirect products of 5-LOcatalysed oxidation of arachidonic acid are involved, and the productionof new medicaments for such use.

As stated above the indazolone derivatives described hereinafter areinhibitors of 5-LO, which enzyme is known to be involved in catalysingthe oxidation of arachidonic acid to give rise via a cascade process tothe physiologically active leukotrienes such as leukotriene B₄ (LTB₄)and the peptido-lipid leukotrienes such as leukotriene C₄ (LTC₄) andleukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trendsin Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes andtheir metabolites have been implicated in the production and developmentof various inflammatory and allergic diseases such as arthriticdiseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis,cardiovascular and cerebrovascular disorders and inflammatory boweldisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolites of arachidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

In copending European Application No. 88300281.8 (published 28th Sept.,1988 as EP 0284174 Al) it is disclosed that certain indazolonederivatives are effective as inhibitors of the enzyme 5-LO and thus ofleukotriene biosyntheses. It has subsequently been shown that certaincompounds within the scope of that application possess redox properties,which properties may contribute to the inactivation of the enzyme 5-LOby reduction of an iron atom within the active site from the ferric (Fe(III)) to the ferrous (Fe (II)) oxidation level. However some redoxinhibitors are known to induce methaemoglobin formation (F L Fort etalia, Fundamental and Applied Toxicology, 1984, 4, 216) and it has nowbeen discovered that 1,2-dihydro-2-(3-pyridylmethyl) 3H indazol-3-one(Ex. 24 of EP 0284174 Al) when dosed orally to dogs at a dose of 5 mg/kgcauses induction of methaemoglobin formation. There is therefore a needfor an inhibitor of the enzyme 5-LO which does not possess thispotentially serious side-effect.

We have now discovered that certain indazolone derivatives are effectiveas inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses.Moreover the indazolone derivatives of the invention do not cause theinduction of significant levels of methaemoglobin at doses which producesignificant inhibition of the enzyme 5-LO. Thus, such compounds are ofvalue as therapeutic agents in the treatment of, for example, allergicconditions, asthma, cardiovascular and cerebrovascular disorders, and/orinflammatory and arthritic conditions, mediated alone or in part by oneor more leukotrienes.

According to the invention there is provided a1,2-dihydro-3H-indazol-3-one (hereinafter abbreviated to indazolone)derivative of the formula I (set out hereinafter) wherein

Ra is hydrogen, halogeno, hydroxy, cyano, trifluoromethyl, (1-6C)alkylor (1-6C)alkoxy;

Rb is hydrogen or (1-6C)alkyl;

Rc is hydrogen, (1-8C)alkyl or (3-8C)alkenyl: and

Y is (1-8C)alkyl, (3 8C)alkenyl or (3-8C)alkynyl, or

Y is a group of the formula A Q in which A is (1 6C)alkylene or(3-6C)alkenylene, and Q is phenyl, naphthyl, pyridyl, thienyl,isoxazolyl, thiazolyl or thiadiazolyl, which may optionally bear one ortwo substituents selected from halogeno, hydroxy, cyano,trifluoromethyl, amino, nitro, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di[(1-4C)alkyl]amino or (2-6)alkanoylamino, or Q maybear a (1-4C)alkylenedioxy substituent;

or a pharmaceutically-acceptable salt thereof;

or a (1-4C)alkoxycarbonyl derivative thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter. In this specificationthe term "alkyl" includes both straight and branched alkyl groups butreferences to individual alkyl groups such as "propyl" are specific forthe straight chain ("normal") version only, any branched chain isomersuch as "isopropyl" being referred to specifically. An analogousconvention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds offormula I or their (1-4C)alkoxycarbonyl derivatives defined above mayexist in optically active or racemic forms by virtue of one or moresubstituents containing an asymmetric carbon atom, the inventionincludes in its definition of active ingredient any such opticallyactive or racemic form which possesses the property of inhibiting 5-LO.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against 5-LO may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for Ra, or for Rb when it is (1-6C)alkyl, include thefollowing, by way of example:

for halogeno: fluoro, chloro, bromo and iodo;

for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and butyl; and

for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy.

A suitable value for Rc or Y when it is (1-8C)alkyl is, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,isopentyl, hexyl, heptyl or octyl; when it is (3-8C)alkenyl is, forexample, allyl, methylallyl, 2-butenyl, 3-butenyl, 3-methylbut-2-enyl or2-hexenyl; or when it is (3-8C)alkyl is, for example, 2-propynyl,2-butynyl, 3-butynyl or 2-hexynyl.

A suitable value for A when it is (1-6C)alkylene is, for example,methylene, ethylene, ethylidene, trimethylene, propylidene,tetramethylene or pentamethylene; or when it is (3-6C)alkenylene is, forexample, 2-propenylene, 2-butenylene or 3-butenylene.

Suitable values for Q when it is naphthyl, pyridyl, thienyl, isoxazolyl,thiazolyl or thiadiazolyl include, for example, 1-naphthyl, 2-naphthyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,1,2,5-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazol-5-yl.

Suitable values for optional substituents which may be present on Qinclude, for example

for halogeno: fluoro, chloro and bromo;

for (1-6C)alkyl: methyl, ethyl, propyl and butyl;

for (1-6C)alkoxy: methoxy, ethoxy, isopropoxy and butoxy;

for (1-6C)alkylamino: methylamino, ethylamino, propylamino andbutylamino;

for di-[(1-4C)alkyl] amino: dimethylamino, diethylamino anddipropylamino;

for (2-6C)alkanoylamino: acetamido, propionamido, butyramido andhexanamido; and

for (1-4C)alkylenedioxy: methylenedioxy and ethylenedioxy.

A suitable value for a (1-4C)alkoxycarbonyl derivative of an indazoloneof the formula I is, for example, a methoxycarbonyl, ethoxycarbonyl or tbutoxycarbonyl derivative in which the alkoxycarbonyl group is locatedon Nl of the indazolone ring.

Suitable pharmaceutically acceptable salts include, for example, alkalimetal (such as potassium or sodium), alkaline earth metal (such ascalcium or magnesium), ammonium and aluminium salts, and salts withorganic bases affording physiologically acceptable cations, such assalts with methylamine, dimethylamine, trimethylamine, piperidine andmorpholine. In addition, for those indazolone derivatives which aresufficiently basic, suitable pharmaceutically-acceptable salts includephysiologically-acceptable acid-addition salts such as salts withhydrogen halides, sulphuric acid and phosphoric acid.

A preferred compound of the invention comprises an indazolone of theformula I wherein

Ra is hydrogen, fluoro, chloro, bromo, methyl, ethyl or methoxy;

Rb is hydrogen, methyl or ethyl;

Rc is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

pentyI, hexyI, aIIyI oz methyIaIIyl; and

Y is methyl, ethyl. propyl, butyl, allyl or methylallyl, or Y is a groupof the formula--A--Q wherein A is methylene, ethylene, ethylidene,trimethylene, ethylidene or 2-propenylene, and Q is phenyl, naphth 1-yl,3-pyridyl, 4-pyridyl, 5-thiazolyl or 1,2,5-thiadiazol-3-yl, which mayoptionally bear fluoro, chloro, bromo, amino, methyl, ethyl or methoxy;

or a pharmaceutically acceptable salt thereof;

or a (1-4C)alkoxycarbonyl derivative thereof.

An especially preferred compound of the invention comprises

an indazolone of the formula I wherein Ra is hydrogen; Rb is hydrogen:

Rc is methyl, ethyl, propyl, butyl or pentyl; and

Y is methyl or ethyl, or

Y is a group of the formula--A--Q wherein A is methylene and Q is phenylor 3-pyridyl;

or a pharmaceutically-acceptable salt thereof:

or a (1-4C)alkoxycarbonyl derivative thereof.

A specific especially preferred compound of the invention is, forexample, a compound selected from the group consisting of2-methyll-4-(N-methylcarbamoyl) , 2-methyll-4-(N-ethylcarbamoyl) ,2-methyll-4-(N-n-pentylcarbamoyl) , 2-benzyl 4-(N-n-pentylcarbamoyl) ,4-(N methylcarbamoyl) 2-(3-pyridylmethyl) , 4-(N ethylcarbamoyl)2-(3-pyridylmethyl) and 4-(N-n-pentylcarbamoyl) 2-(3-pyridylmethyl)1,2-dihydro-3H-indazol 3-one; or a pharmaceutically-acceptable saltthereof; or a (1-4C)alkoxycarbonyl derivative thereof.

The compounds of the formula I may be obtained by conventionalprocedures of organic chemistry well known in the art for themanufacture of structurally analogous indazolones. Thus, for example,they may be obtained by the procedures analogous to those disclosed in"The Chemistry of Heterocyclic Compounds", (ed. R. H. Wiley, publishedby Interscience 1967), Vol. 22, Chapter 10, at pages 356-361, in "TheHeterocyclic Compounds". (ed. R. C. Elderfield, published by Wiley1957), Vol. 5, at pages 166-182, and in the article by L. Baiocchi andG. Palazzo (Synthesis, 1978, 633-648), the contents of whichpublications are incorporated herein by way of reference. The inventionfurther includes the manufacture of an indazolone of the formula I, orof a (1-4C)alkoxycarbonyl derivative thereof, or of apharmaceutically-acceptable salt thereof, by any one of such analogousprocedures.

In particular, the invention includes the manufacture of an indazoloneof the formula I as defined above by a process (a) which comprisesdeprotecting a protected indazolone derivative of the formula II whereinRa, Rb, Rc and Y have the meanings defined hereinbefore and Rd is aprotecting group.

Suitable examples of protecting groups Rd include, for example, acylgroups such as (1-4C)alkanoyl (especially acetyl), (1-4C)alkoxycarbonyl(especially methoxcarbonyl, ethox butoxycarbonyl) and aroyl (especiallybenzoyl). The deprotection conditions used for the above processnecessarily vary with the nature of Rd. Thus, for example, acyl groupssuch as alkanoyl, alkoxycarbonyl and aroyl may be removed by, forexample, hydrolysis with base such as an alkali metal hydroxide (forexample lithium or sodium hydroxide) or acid such as hydrochloric,sulphuric or phosphoric acid, generally in the presence of an aqueoussolvent or diluent such as a (1-4C)alkanol and at a temperature in therange, for example, 0° to 60° C. (conveniently at or about roomtemperature). It will be appreciated that, when a base is used for thedeprotection, the indazolone is initially formed as the correspondingsalt from which the free indazolone may be liberated by a conventionalacidification process, for example by treatment with a mineral acid suchas hydrochloric acid. The process is particularly adapted to theproduction of those compounds of formula I wherein Y is alkyl, alkenylor a group--A-- Q as previously defined. Alternatively acyl groups suchas alkanoyl, alkoxycarbonyl and aroyl may be removed by, for example,treatment with base such as ammonia or a (1-4C)alkylamine (for examplemethylamine), generally in the presence of a diluent such as a(1-4C)alkanol and at a temperature in the range, for example, 0° to 80°C. (conveniently at or about room temperature).

The starting material of the formula II may be conveniently obtained,for example, by protecting an indazolone derivative of the formula III,for example by reacting it with a suitable acyl halide, or anhydride,such as a (1-4C)alkanoyl chloride or bromide, a (1-4C)alkanoic acidanhydride, benzoyl chloride, benzoic acid anhydride, or a(1-4C)alkoxycarbonyl chloride (which is preferred) under conventionalacylation conditions, for example in the presence of a suitable basesuch as pyridine, 4-dimethylaminopyridine, triethylamine, morpholine orN methylmorpholine, to give a protected derivative of the formula IVwherein Rd has the meanings defined above. The latter derivative maythen be reacted with an alkylating agent of the formula L-Y wherein L isa leaving group and Y has the meaning defined hereinabove. Suitableleaving groups, when Y is alkyl or alkenyl, or is a group of theformula--A--Q include, for example, halogeno (especially chloro, bromoor iodo) and alkane- or arenesulphonyloxy (especially methansulphonyloxyor p-toluenesulphonyloxy). The alkylation reaction is preferablyperformed in the presence of a suitable base, for example an alkalimetal hydroxide, in a suitable inert solvent or diluent, for example tbutyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane, Nmethylpyrrolidone or N,N-dimethylformamide. Alternatively, the protectedindazolone derivative of the formula IV may be used in the form of itspreformed anhydrous alkali metal salt, for example by prior reactionwith a molecular equivalent of a suitable base such as sodium orpotassium methoxide, ethoxide or hydride or butyl-lithium; in which casea wider range of conventional solvents such as (1-4C)alkanol diluentsmay be employed for the reaction with the alkylating agent of formula LY. This procedure is particularly useful when Rd is a(1-4C)alkoxycarbonyl group. In either case, the alkylation is generallyperformed at a temperature in the range, for example, 10° to 100° C.and, conveniently, at or near ambient temperature.

It is to be understood that the reaction of a protected derivatives ofthe formula IV with an alkylating agent of the formula L-Y may, inaddition, give rise to a compound isomeric with that of the formula II,i.e. in which Y is attached to the oxygen atom of the amide group. Suchisomeric compounds may be separated by procedures well known to thoseskilled in the art, for example by column chromatography or bycrystallisation.

The starting indazolone derivative of the formula III may be made byanalogy with known indazolone synthetic procedures.

A further process (b) according to the invention for the manufacture ofan indazolone of the formula I as defined hereinbefore comprisescyclising a 2-hydrazino-benzoic acid of the formula V, or a reactivederivative thereof, wherein Ra, Rb, R and Y have the meanings definedabove.

The cyclisation may be carried out using a variety of conditions. Forexample, it may be carried out thermally by heating the free carboxylicacid at a temperature in the range, for example, 40°-120° C., under theinfluence of an acid catalyst such as acetic acid, propionic acid or amineral acid (for example hydrochloric, sulphuric or phosphoric acid).Alternatively, the free carboxylic acid may be converted to a reactivederivative such as an acid halide, for example using phosphorylchloride, oxalyl chloride or thionyl chloride at a temperature in therange, for example, 10° to 60° C., which halide may in certain casesspontaneously cyclise to the required indazolone of the formula I. Analternative reactive derivative of the carboxylic acid of the formula Vis, for example, a (1-4C)alkyl, phenyl or benzyl ester of said acid,which derivatives may be cyclised, for example, by the influence ofheat, optionally in the presence of an acidic or basic catalyst.

The starting 2-hydrazinobenzoic acid of the formula V may be obtained,by standard procedures of organic chemistry. Thus, for example, thecompound of the formula V wherein Y is a group of the formula --CH₂.A¹⁻⁻Q in which A¹ is a direct link to Q, (1-5C)alkylene or (2-5C)alkenyleneand Q has the meaning defined hereinbefore or Y is a group of theformula --CH₂.Y¹ in which Y¹ is hydrogen, (1-7C)alkyl, (2-7C)alkenyl or(2-7C)alkynyl, may be obtained by reduction of a hydrazone of theformula VIa or VIb, for example using an alkali metal amalgam,borohydride or cyanoborohydride (especially sodium cyanoborohydride) ina suitable solvent or diluent such as a (1-4C)alkanol (for exampleethanol or methanol) or an ether (for ex tetrahydrofuran or t butylmethyl ether) at a temperature in the range, for example, 10° to 50° C.The hydrazone of the formula VIa or VIb may itself be obtained by aconventional procedure involving reaction of an aldehyde of the formulaH.CO.A¹.Q or H.CO.Y¹ with a hydrazine of the formula VII. The hydrazineof the formula VII may itself be obtained, for example, by aconventional reduction of a diazonium salt derived from thecorresponding 2-aminobenzoic acid, for example using sodium sulphite,sulphur dioxide or stannous chloride as a reducing agent. The necessary2-aminobenzoic acids and the aldehydes of the formula H.CO.A¹ Q orH.CO.Y¹ are in general known or may be obtained by standard proceduresof organic chemisty.

As will readily be appreciated process (b) is particularly suitable forthe production of those compounds of the formula I wherein Y is a groupof the formula --CH₂ Q or CH₂ Y¹ as defined above.

A further process (c) according to the invention for the manufacture ofan indazolone of the formula I comprises cyclising a 2-aminobenzamidederivative of the formula VIII wherein Z is a suitab leaving group, forexamnle hydroxy, acetoxy, methoxy or p-toluenesulphonyloxy.

The cyclisation may be carried out using a variety of conditions. Forexample, it may be carried out under conventional acid or base catalysis(which latter is generally preferred) at a temperature in the range, forexample 40° to 120° C., in a suitable solvent or diluent, for example a(1-4C)alkanol (such as methanol or ethanol). A suitable base is, forexample, an alkali metal hydroxide or (1-4C)alkoxide, such as sodiumhydroxide, potassium hydroxide, sodium methoxide or potassium ethoxide.

The starting material of the formula VIII can be made by standardtechniques of organic chemistry. Thus, for example, the compound of theformula VIII wherein Z is hydroxy may be obtained by reduction of thecorresponding nitro compound of the formula IX using conditions known toproduce the required hydroxylamine, for example using zinc or iron dustin the presence of a base such as an alkali metal hydroxide or ammoniumacetate, at a temperature in the range, for example, 10° to 50° C. andin a suitable aqueous solvent of diluent such as methanol or ethanol.

The production of an indazolone of the formula I may therefore also becarried out by the preferred procedure of reacting a nitro compound ofthe formula IX with a suitable reducing metal, such as zinc or irondust, in the presence of a strong base, such as an alkali metalhydroxide, in a suitable solvent or diluent such as a (1-4C)alkanol(e.g. methanol or ethanol, of which the latter is preferred), and at atemperature in the range, for example, 40° to 120° C.

The starting material of the formula IX may be obtained from thecorresponding carboxylic acid of the formula X and the amine of theformula H₂ N.Y using conventional amidification procedures which arestandard techniques of organic chemistry.

A further process (d) according to the invention for the manufacture ofan indazolone of the formula I which contains one or more phenolichydroxy groups comprises deprotecting a suitably protected version ofsuch a compound of the formula I.

Suitable phenolic hydroxy protecting groups include, for example,(1-6C)alkyl, (3-6C)alk-2-enyl, tri(1-4C)alkylsilyl,tetrahydropyran-2-yl, 1-aryl-(1-4C)alkyl, (1-6C)alkanoyl and aroyl (suchas methyl, ethyl, t butyl, allyl, trimethylsilyl, tetrahydropyran-2-yl,benzyl, 1-phenylethyl, formyl, acetyl and benzoyl).

The deprotection reaction conditions necessarily depend on theprotecting group used. However, in general, conditions which arestandard in the art for the removal of the same protecting group inchemically analogous compounds are used. Thus, for example, when theprotecting group is (1-6C)alkyl (and especially methyl) the deprotectionmay be carried out, for example, by use of boron tribromide at -80° C.to 20° C., optionally in a suitable solvent such as methylene chloride,or by heating with sodium thioethoxide in a suitable solvent, such asN,N-dimethylformamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone, at a temperature of, for example, 50° to 160° C.Alternatively, an ethyl or methyl protecting group may be removed, forexample, by reaction with lithium diphenylphosphide in a suitablesolvent or diluent, such as tetrahydrofuran or t butyl methyl ether, ata temperature in the range, for example, 0° to 60° C. Similarly, analkanoyl or benzoyl protecting group may be removed, for example, bybase catalysed hydrolysis (such as sodium or potassium hydroxide in anaqueous (1-4C)alkanol or glycol) at a temperature, for example, in therange 10° to 60° C. Similarly, an allyl or tetrahydropyran-2-ylprotecting group may be removed, for example, by a conventionaltreatment with a strong acid such as trifluoroacetic acid. Similarly, atrimethylsilyl protecting group may be removed, for example, byconventional treatment with aqueous tetrabutylammonium fluoride orsodium fluoride, and a benzyl or 1-phenylethyl protecting group, forexample, by treatment with sodium in liquid ammonia.

The necessary protected derivatives are obtainable by analogousprocedures to those described hereinbefore or by modifications theretowithin the ordinary skill of an organic chemist.

A further process (e) according to the invention for the production ofan indazolone of the formulae I or II which contains one or twoalkanoylamino groups comprises acylating a compound of the formula I ora compound of the formula II which contains one or two amino groups.

A particular suitable acylating agent is, for example, any agent knownin the art for the acylation of amino to acylamino, for example an acylhalide, for example a (2-6C)alkanoyl chloride or bromide, in thepresence of a suitable base, an alkanoic acid anhydride, for example a(2-6C)alkanoic acid anhydride, or an alkanoic acid mixed anhydride, forexample the mixed anhydride formed by the reaction of an alkanoic acidand a (1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonylchloride, in the presence of a suitable base. In general the reaction iscarried out in a suitable solvent or diluent such as methylene chloride,acetone, tetrahydrofuran or t-butyl methyl ether and at a temperture,for example, at or near ambient temperature, that is in the range 15° to35° C. A suitable base when it is required is, for example, pyridine,4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine,N-methylmorpholine, an alkali metal carbonate, for example potassiumcarbonate, or an alkali metal carboxylate, for example sodium acetate.It will be appreciated that when a compound of the formula I whichcontains one or two amino groups is subjected to reaction with anacylating agent there may be, in addition to acylation of the aminogroup, acylation of the unprotected nitrogen atom in the indazolonering. It is well known to one skilled in the art how to separate suchmixtures of compounds, for example by column chromatography or bycrystallisation. It will also be appreciated that when a compound of theformula II is acylated a novel compound of the formula I can be producedby deprotecting the protected indazolone using conditions describedunder process (a) above.

A further process (f) according to the invention for the production ofan indazolone of the formula I wherein Y is a group of the formula A--Qand there are one or two amino substituents in Q, comprises thereduction of the corresponding compound wherein there are one or twonitro substituents in Q. In general conditions which are standard in theart for the reduction of a nitro group are used. Thus, for example, thereduction may be carried out by the hydrogenation of a solution of thenitro compound in an inert solvent or diluent in the presence of asuitable metal catalyst, for example finely divided platinum metal(obtained by the reduction of platinum oxide in situ). A suitable inertsolvent or diluent is, for example, an alcohol, for example methanol,ethanol or isopropanol, or an ether, for example tetrahydrofuran ort-butyl methyl ether. The reaction is generally carried out at atemperature at or near ambient temperature, that is in the range 15° to35° C.

A further process (g) according to the invention for the production ofan indazolone of the formula I wherein Y is a group of the formula--A--Qand wherein A is alkenylene comprises the reduction of the correspondingcompound wherein A is alkynylene. In general conditions which arestandard in the art for the reduction of an alkynylene group are used.Thus, for example, the reduction may be carried out by the hydrogenationof a solution of the alkynylene compound in an inert solvent or diluentin the presence of a suitable metal catalyst. A suitable inert solventis, for example, an alcohol, for example methanol or ethanol, or anether, for example tetrahydrofuran or t-butyl methyl ether. A suitablemetal catalyst is, for example, palladium or platinum on an inertsupport, for example charcoal or barium sulphate. Preferably apalladium-on-barium sulphate catalyst is used to substantially preventover-reduction of the alkynylene group to an alkylene group. Thereaction is generally carried out at a temperature at or near ambienttemperature, that is in the range 15° to 35° C.

When a pharmaceutically-acceptable salt of an indazolone of the formulaI is required, it may be obtained, for example, by reaction of saidcompound with a suitable acid or base using a conventional procedure.When an optically active form an indazolone of the formula I is requiredit may be obtained by carrying out one of the aforesaid procedures usingan optically active starting material, or by resolution of a racemicform of said compound using a conventional procedure.

As stated previously, the indazolones of the formula I are inhibitors ofthe enzyme 5-LO. The effects of this inhibition may be demonstrated, forexample, using one or more of the standard procedures set out below:

(a) An in vitro spectrophotometric enzyme assay system, which assessesthe inhibitory properties of a test compound in a cell free system using5-LO isolated from guinea pig neutrophils and as described by D. Aharonyand R. L. Stein (J. Biol. Chem., 1986, 261(25), 11512-11519). This testprovides a measure of the intrinsic inhibitory properties againstsoluble 5-LO in an extracellular environment.

(b) An in vitro assay system involving incubating a test compound withheparinised rat blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using the specific radioimmunoassaydescribed by Carey and Forder (F. Carey and R. A. Forder, Brit. J.Pharmacol. 1985, 84, 34P) which involves the use of a protein-LTB₄conjugate produced using the procedure of Young et alia Prostaglandins,1983, 26(4), 605-613). The effects of a test compound on the enzymecyclooxygenase (which is involved in the alternative metabolic pathwayfor arachidonic acid and gives rise to prostaglandins, thromboxanes andrelated metabolites) may be measured at the same time using the specificradioimmunoassay for prostaglandin E₂ (PGE₂) described by Carey andForder (see above). This test provides an indication of the effects of atest compound against 5-LO and also cyclooxygenase in the presence ofblood cells and proteins. It permits the selectivity of the inhibitoryeffect on 5-LO or cyclooxygenase to be assessed.

(c) An ex vivo assay system, which is a variation of test b) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and PGE₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

(d) An in vitro assay system involving the measurement of the inhibitoryproperties of a test compound against the liberation of LTC₄ and PGE₂induced by zymosan on mouse resident peritoneal macrophages, using theprocedure of Humes (J. L. Humes et alia, Biochem. Pharmacol 1983, 32,2319-2322) and conventional radioimmunoassay systems to measure LTC₄ andPGE₂. This test provides an indication of inhibitory effects against5-LO and cyclooxygenase in a non-proteinaceous system.

(e) An in vivo system involving the measurement of the effects of a testcompound in inhibiting the inflammatory response to arachidonic acid inthe rabbit skin model developed by D. Aked et alia (Brit. J. Pharmacol.,1986, 89, 431-438). This test provides an in for 5-LO inhibitorsadministered topically or orally.

(f) An in vivo system involving measuring the effects of a test compoundadministered orally or intravenously on a leukotriene dependentbronchoconstriction induced by an antigen challenge in guinea pigspre-dosed with an antihistamine (mepyramine), a β-adrenergic blockingagent (propranolol) and a cyclooxygenase inhibitor (indomethacin), usingthe procedure of W. H. Anderson et alia (British J Pharmacology, 1983,78(1), 67-574). This test provides a further in vivo test for detecting5-LO inhibitors.

Although the pharmacological properties of the indazolones of theformula I necessarily vary with structural changes, in general compoundsof the formula I possess 5-LO inhibitory effects at the followingconcentrations or doses in one or more of the above tests (a)-(f):

Test (a): IC₅₀ in the range, for example, 0.1-30μM;

Test (b): IC₅₀ (LTB₄) in the range, for example, 0.1-10μM IC₅₀ (PGE₂) inthe range, for example, 15-200μM;

Test (c): oral ED50 (LTB₄) in the range, for example, 1-200 mg/kg;

Test (d): IC₅₀ (LTC₄) in the range, for example, 0.001-1μM, IC₅₀ (PGE₂)in the range, for example, 20-1000μM;

Test (e): inhibition of inflammation in the range, for example,0.3-100μg intradermally:

Test (f): ED₅₀ in the range, for example, 0.5-10mg/kg i.v.

No overt toxicity or other untoward effects are present in tests (c),(e) and or (f) when compounds of the formula I are administered atseveral multiples of their minimum inhibitory dose or concentration. Inaddition, using conventional tests for the measurment of methaemoglobinformation, it was shown that no significant induction of methaemoglobinformation is caused when compounds of the formula I are administered atseveral multiples of the minimum inhibitory dose or concentration forthe inhibition of the enzyme 5-LO.

Thus, by way of example, the compound1,2-dihydro-2-methyll-4-(N-n-pentylcarbamoyl)-3Hindazol-3-one has anIC₅₀ of 3.1μM in test (a), and IC₅₀ pf 1.4μM against LTB₄ and of 72μMagainst PGE₂ in test (b), and an oral ED50 of 30-100 mg/kg versus intest (c). In general those compounds of the formula I which areparticularly preferred have an IC₅₀ of <μM against LTB₄ and of >50μMagainst PGE₂ in test (b), and an oral ED₅₀ of <100 mg/kg against LTB₄ intest (c).

These compounds are examples of indazolones of the invention which showselective inhibitory properties for 5-LO as opposed to cyclooxygenase,which selective properties are expected to impart improved therapeuticproperties, for example, a reduction in or freedom from thegastrointestinal side-effects frequently associated with cyclooxygenaseinhibitors such as indomethacin.

According to a further feature of the invention there is provided apharmaceutical composition which comprises an indazolone of the formulaI, or a pharmaceutically-acceptable salt thereof, or a(1-4C)alkoxycarbonyl derivative thereof, as defined hereinbefore, inassociation with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fornasal use, for example a snuff, nasal spray or nasal drops; for vaginalor rectal use, for example a suppository; for administration byinhalation, for example as a finely divided powder or a liquid aerosol:for sub-lingual or buccal use, for example a tablet or capsule; or forparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The amount of active ingredient (that is an indazolone of the formula I,or a pharmaceutically-acceptable salt thereof, or a (1-4C)alkoxycarbonylderivative thereo(f) that is combined with one or more excipients toproduce a single dosage form will necessarily vary depending upon thehost treated and the particular route of administration. For example, aformulation intended for oral administration to humans will generallycontain, for example, from 0.5 mg to 2 g of active ingredient compoundedwith an appropriate and convenient amount of excipients which may varyfrom about 5 to about 8 percent by weight of the total composition.Dosage unit forms will generally contain about 1 mg to about 500 mg ofan active ingredient.

The invention also includes an active ingredient as defined above foruse in medicine. By for use in medicine both prophylactic andtherapeutic use of said active ingredient are encompassed.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of amactive ingredient as defined above will naturally vary according to thenature and severity of the conditions, the age and sex of the animal orpatient and the route of administration, according to well knownprinciples of medicine. As mentioned above, indazolones of the formula Iare useful in treating those allergic and inflammatory conditions whichare due alone or in part to the effects of the metabolites ofarachidonic acid arising by the linear (5-LO catalyse(d) pathway and inparticular the leukotrienes, the production of which is mediated by5-LO. As previously mentioned, such conditions include, for example,asthmatic conditions, allergic reactions, allergic rhinitis, allergicshock, psoriasis, atopic dermatitis, cardiovascular and cerebrovasulardisorders of an inflammatory nature, arthritic and inflammatory jointdisease, and inflammatory bowel diseases.

In using an active ingredient as defined above for therapeutic orprophylactic purposes it will generally be administered so that a dailydose in the range, for example, 0.5mg to 75mg per kg body weight isreceived, given if required in divided doses. In general lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous administration, a dose in the range, forexample, 0.5mg to 30 mg per kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.5 mg to 25 mg per kg body weight will be used.

Although indazolones of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, indazolones of theformula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylicacid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises an indazolone ofthe formula I, or a pharmaceutically-acceptable salt thereof, or a(1-4C)alkoxycarbonyl derivative thereof as defined hereinbefore, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent (such as mentioned abov(e), and apharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of an indazolone of the formula I may bedemonstrated, for example, in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionat(e), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporations in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-20° and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedur(e) and mediumpressure liquid chromatography (MPLC) were performed on Herck Kieselgelsilica (Art. 9385 obtained from E. Meck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end products of the formula I have satisfactory microanalysesand their structures were confirmed by NMR and mass spectral techniques;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;and

(vii) melting points are uncorrected and were determined using a Kofflerblock apparatus: melting points for the end-products of the formula Iwere determined after recrystallisation from a conventional organicsolvent such as ethanol, methanol, acetone, ether or hexane, alone or inadmixture.

EXAMPLE 1

1,2-Dihydro-1-carboethoxy-4-(N-methylcarbamoyl)-3-H-indazol-3-one one(3.84 g) was added portionwise to a stirred suspension of sodium hydride[50% w/w dispersion in oil, 0.7 g, from which the oil was washed usingpetrol (b.p. 60°-80° C.)] in dimethylformamide (20 ml) and the mixturewas stirred at ambient temperature for 30 minutes. Methyl iodide (1.1ml) was added and the mixture was stirred at ambient temperature for 1hour. Water (50 ml) and 0.1 N aqueous hydrochloric acid solution wasadded to bring the mixture to pH 6 and the mixture was extracted withethyl acetate (3×50 ml). The combined organic extracts were washed withsaturated aqueous sodium chloride solution, dried (MgSO₄) andevaporated. The residue was triturated under a mixture of petrol (b.p.60°-80° C.) and diethyl ether and the solid product was filtered off.There was thus obtained1,2-dihydro-1-carboethoxy-2-methyll-4-(N-methylcarbamoyl)-3H-indazol-3-one(3.4 g, 78%) m.p. 132+-134° C.

A solution of the material so obtained (1.15 g) in methanol (20 ml) wasstirred at ambient temperature and gaseous methylamine was bubbled intothe solution for 5 minutes. The mixture was then stirred at ambienttemperature for 30 minutes. The mixture was evaporated and the residuewas purified by column chromatography eluting with a 19/1 v/v mixture ofmethylene chloride and methanol. There was thus obtained1,2-dihydro-2-methyll-4-(N-methylcarbamoyl)-3H-indazol-3-one (0.73 g,86%), m.p. 225°-250° C.

The 1,2-dihydro-1-carboethoxy-4-(N-methylcarbamoyl)-3H-indazol-3-onestarting material was obtained as follows:

A solution of 3-acetoxy-1-acetyl-lH indazole-4-carbonyl chloride[prepared from the corresponding 4-carboxylic acid (10.5 g) using theprocedure described in UK Patent Specification Number 339592 (ChemicalAbstracts, 76, 147252 m)] in methylene chloride (20 ml) was addeddropwise to a mixture of methylamine hydrochloride (3.9 g),triethylamine (12.5 ml) and methylene chloride (100 ml) which had beencooled to 0° C. The mixture was stirred at ambient temperature for 1hour and evaporated. The residue was dissolved in methanol (100 ml), thesolution was saturated with gaseous methylamine and the mixture washeated to reflux for 3 hours. The mixture was evaporated, the residuewas dissolved in water (100 ml) and 1N aqueous hydrochloric acidsolution was added to bring the mixture to pH 4. The precipitated solidwas collected and dried. There was thus obtained1,2-dihydro-4-(N-methylcarbamoyl)-3H-indazol-3-one (5.9 g, 82%), m.p.178°-180° C.

Ethyl chloroformate (6.64-ml) was added dropwise to a mixture of thematerial so obtained (5.9 g) and pyridine (26 ml) which had been cooledto 0° C. The mixture was then heated to reflux for 45 minutes, cooled toambient temperature and poured into water (100 ml). The precipitatedsolid was collected and dried. There was thus obtained1,2-dihydro-1-carboethoxy-4-(N-methylcarbamoyl)-3H-indazol-3-one (7.6 g,94%).

EXAMPLE 2

Using a similar procedure to that described in Example 1 but startingfrom 1,2-dihydro-1-carboethoxy-4-(N-ethylcarbamoyl)-3H-indazol-3-onethere were obtained in turn1,2-dihydro-1-carboxyethoxy-4-(N-ethylcarbamoyl)-2-methyl-3Hindazol-3-oneas a solid, m.p. 129--20 121° C., in 82% yield, and1,2-dihydro-4-(N-ethylcarbamoyl)-2-methyl--3H-indazol-3-one as a solid,m.p. 192°-194° C., in 73% yield.

The starting material was obtained from3-acetoxy-1-acetyl-1H-indazole-4-carbonyl chloride using the proceduredescribed in the corresponding portion of Example 1 except thatethylamine hydrochloride was used in place of methylamine hydrochloride.There were thus obtained in turn 1,2-dihydro-4-(Nethylcarbamoyl)-3H-indazol-3-one as an oil in 100% yield which was usedwithout further Purification and1,2-dihydro-1-carboethoxy-4-(N-ethylcarbamoyl) 3H-indazol-3-one as asolid, m.p. 209°-210° C., in 70% yield.

EXAMPLE 3

3 Picolyl chloride hydrochloride (2 g) was added portionwise to amixture of1,2-dihydro-1-carboethoxy-4-(N-methylcarbamoyl)-3H-indazol-3-one (3 g),cesium carbonate (8.2 g) and dimethylformamide (25 ml) and the mixturewas heated to 50° C. for 1 hour. Acetic acid was added to bring themixture to pH 7 and then the mixture was evaporated. There was thusobtained as a solid1,2-dihydro-1-carboethoxy-4-(N-methylcarbamoyl-2-(3-pyridylmethyl)-3H-indazol-3-one(1.8 g, 47%) which was used without further purification.

The product so obtained was treated with methylamine using the proceduredescribed in the second paragraph of Example 1. There was thus obtained1,2-dihydo-4-(N-methylcarbamoyl)-2-(3-pyridylmethyl)-3H-indazol-3-one asa solid, m.p. 182°-184° C., in 72% yield.

EXAMPLE 4

Using a similar procedure to that described in the first paragraph ofExample 3 but starting from1,2-dihydro-1-carboethoxy-4-(N-ethylcarbamoyl)-3H-indazol-3-one therewas obtained1,2-dihydro-1-carboethosy-4-(N-ethylcarbamoyl)-2-(3-pyridylmethyl(3H-indazol-3-oneas an oil in 54% yield.

The product so obtained was treated with methylamine using the proceduredescribed in the second paragraph of Example 1. There was thus obtained1,2-dihydro-4-(N-ethylcarbamoyl)-2-3-pyridylmethyl)-3H-indazol-3-one asa solid, m.p. 197°-198° C., in 50% yield.

EXAMPLE 5

Using a similar procedure to that described in the first paragraph ofExample 1 but starting from1,2-dihydro-1-carboethoxy-4-(N-n-pentylcarbamoyl)-3Hindazol-3-one therewas obtained1,2-dihydro-1-carboethoxy-2-methyl-4-(N-n-pentylcarbamoyl)-3H-indazol-3-oneas an oil in 100% yield.

A mixture of the product so obtained (4 g), 2N aqueous sodium hydroxidesolution (12 ml) and methanol (40 ml) was heated to 50° C. for 15minutes. The mixture was evaporated. Water (30 ml) was added, 1N aqueoushydrochloric acid solution was added to bring the mixture to pH 3 andthe mixture was extracted with ethyl acetate (3×50 ml). The combinedorganic extracts were washed with a saturated aqueous sodium chloridesolution, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography eluting with a 19/1 v/v mixture of methylenechloride and methanol. There was thus obtained1,2-dihydro-2-methyl-4-(N-n-pentylcarbamoyl)-3H-indazol-3-one (2.13 g,68%), m.p. 128°-129° C. recrystallised from a mixture of water andethanol).

The 1,2-dihydro-1-carboethoxy-4-(N-n-entylcarbamoyl)-3Hindazol-3-onestarting material was obtained as follows:

A solution of 3-acetoxy-1-acetyl-1H-indazole-4-carbonyl chloride[prepared from the corresponding 4-carboxylic acid (1.8-g) using theprocedure described in UK Patent Specification Number 133959] inmethylene chloride (10 ml) was added dropwise to a mixture ofn-pentylamine (0.88 ml) and triethylamine (12.5 ml). The mixture wasstirred at ambient temperature for 1 hour and evaporated. The residuewas dissolved in ethyl acetate (25 ml), washed with 0.1N aqueoushydrochloric acid solution and evaporated. The residue was dissolved inmethanol (5 ml) and 1N aqueous sodium hydroxide solution (3.5 ml) wasadded. The mixture was stirred at ambient temperature for 15 minutes,poured into water (10 ml), acidified with 1N aqueous hydrochloric acidsolution and extracted with ethyl acetate (3×25 ml). The combinedorganic extracts were washed with water, dried (MgSO₄) and evaporated.The residue was purified by column chromatography eluting with a 19/1v/v mixture of methylene chloride and methanol. There was thus obtained1,2-dihydro-4-(N-N-pentylcarbamoyl)-3H-indazol-3-one (1.22 g, 77%), m.p.167°-169° C.

The material so obtained was treated with ethyl chloroformate using theprocedure described in the second paragraph of the portion of Example 1which is concerned with the preparation of the starting material. Therewas thus obtained1,2-dihydro-1-carboethoxy-4-(N-n-pentylcarbamoyl)-3H-indazol-3-one as asolid, m.p. 145°-146° C., in 78% yield.

These reactions were repeated to give the required quantity of startingmaterial.

EXAMPLE 6

A mixture of1,2-dihydro-1-carboethoxy-4-(N-n-pentylcarbamoyl)-3H-indazol-3-one (1g),benzyl bromide (0.74 ml), sodium iodide (45 mg), triethylamine (0.87 ml)and chloroform (40 ml) was heated to reflux for 10 hours. The mixturewas evaporated and petrol (b.p. 60-80oC) was added to the residue. Themixture was filtered and the filtrate was evaporated to give a mixtureof1,2-dihydro-2-benzyl-1-carboetheoxy-4-(N-n-pentylcarbamoyl)-3H-indazol-3-oneand 3-benzyloxy-1-carboethoxy-4-(N-n-pentylcarbamoyl)-1H-indazole as anoil (0.87 g, 68%) which was used without further purification.

The mixture so obtained was treated with an aqueous sodium hydroxidesolution using the procedure described in the second paragraph ofExample 5. There was thus obtained 1,2-dihydro-2-benzyl-4-(N-n-pentylcarbamoyl)-3H-indazol-3-one as a solid,m.p. 121°-121° C., in 67% yeild.

EXAMPLE 7

A solution of diisopropyl azodicarboxylate (4.96 g) in tetrahydrofuran(40 ml) was added dropwise to a mixture of1,2-dihydro-1-carboethoxy-4-(N-n-pentylcarbamoyl)-3H-indazol-3-one (5.35g), triphenylphosphine (6.6 g), 3-hydroxymethylpyridine (2 g) andtetrahydrofuran (60 ml). The mixture was stirred at ambient temperaturefor 40 minutes and evaporated. The residue was dissolved in ethylacetate (100 ml) and extracted with 2N aqueous hydrochloric acidsolution (2×50 ml). The combined aqueous extracts were neutralised bythe addition of aqueous sodium bicarbonate solution and extracted withethyl acetate (3×50 ml). The combined organic extracts were washed withwater, dried (HgSO₄) and evaporated. There was thus obtained a mixtureof1,2-dihydro-1-carboethoxy-4-(N-n-pentylcarbamoyl)-2-(3-pyridylmethyl)-3H-indazol-3-oneand1-carboethoxy-4-(N-n-pentylcarbamoyl-3-(3-pyridylmethoxy)-1H-indzaole asan oil (6.8 g, 98%) which was used without further purification.

The mixture so obtained was treated with an aqueous sodium hydroxidesolution using a similar procedure to that described in the secondparagraph of Example 5 except that the reaction was carried out atambient temperature for 1 hour and 1N aqueous hydrochloric acid solutionwas added to bring the mixture to pH 7. There was thus obtained1,2-dihydro-4-(N-n-pentylcarbamoyl)-2-(3-pyridylmethyl)-3Hindazol-3-oneas a solid, m.p. 112°-117° C., in 20% yield.

    ______________________________________                                                             Chemical                                                                      Formulae                                                 ______________________________________                                         ##STR2##              I                                                       ##STR3##              II                                                      ##STR4##              III                                                     ##STR5##              IV                                                      ##STR6##              V                                                       ##STR7##              VIa                                                     ##STR8##              VIb                                                     ##STR9##              VII                                                     ##STR10##             VIII                                                    ##STR11##             IX                                                      ##STR12##             X                                                      ______________________________________                                         ##STR13##

What we claim is:
 1. A 1,2-dihydro-3H-indazol-3-one derivative of theformula I

    ______________________________________                                                             Chemical                                                                      Formulae                                                 ______________________________________                                                               I                                                       ##STR14##             II                                                      ##STR15##             III                                                     ##STR16##             IV                                                      ##STR17##             V                                                       ##STR18##             VIa                                                     ##STR19##             VIb                                                     ##STR20##             VII                                                     ##STR21##             VIII                                                    ##STR22##             IX                                                      ##STR23##             X                                                      ______________________________________                                         ##STR24##     Ra is hydrogen, haogeno, hydroxy, cyano, Trifluoromethyl, (1-6C)alkyl or     (1-6C)aloxy;

Rb is hydrogen or (1-6C) alkyl; Rc is hydrogen, (1-8C)alkyl or(3-8C)alkenyl; and Y is a group of the formula A-Q in which A is(1-6C)alkylene or (3-6C)alkeneylene, and Q is pyridyl, which mayoptionally ear one or two substitutents selected from halogeno, hydroxy,cyano, trifuloromethyl, amino, nitro, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylamino, di[(1-4C)alkyl]amino or (2-6C)alkanoylamino, or apharmaceutically-acceptable salt thereof; or a 1-(1-4C)alkoxycarbonylderivative thereof.
 2. An indazolone of the formula I as claimed inclaim 1 whereinRa is hydrogen, fluoro, cholor, bromo, methyl, ethyl ormethoxy; Rb is hydrogen, methyl or ethyl; Rc is hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, akkyl or methylallyl;and Y is a group of the formula --A-Q wherein A is methylene, ethylene,ethylidene, trimethylene, ethylidene or 2-propenylene, and Q is3-pyridyl or 4-pyridyl which may be optionally bear a substituentselected from fluoro, chloro, bromo, amino, methyl, ethyl or methoxy; ora pharmaceutically-acceptable salt thereof; or a 1-(1-4C)alkoxycarbonylderivative thereof.
 3. An indazolone of the formula I as claimed inclaim 1 wherein Ra is hydrogen; Rb is hydrogen; Rc is methyl, ethyl,propyl, butyl or pentyl; andY is a group of the formula --A-Q wherein Ais methylene and Q is 3-pyridyl; or a pharmacetuical-acceptable saltthereof; or a 1-(1-4C)alkoxycarbonyl derivative thereof.
 4. A compoundselected from the group consisting of4-(N-methylcarbamoyl)-2-(3-pyridylmethyl)-,4-(N-ethylcarbamoyl)-2-(3-pyridylmethyl)- and4-(N-n-pentylcarbamoyl)-2-(3-pyridylmethyl)-1,2-dihydro-3H-indazol-3-one;or a pharmaceutically-acceptable salt thereof; or a1-(1-4C)alkoxycarbonyl derivative thereof.
 5. A pharamceuticalcomposition which comprises an indazolone of the formula I as claimed inany one of claims 1 to 3, or a pharmaceutically-acceptable salt thereof,or a 1-(1-4C)alkoxycarbonyl derivative thereof, in association with apharmaceutically-acceptable diluent or carrier.
 6. An indazolone of theformula I as claimed in any one of claim 1 to 3 or apharmaceutically-acceptable salt thereof, or a 1-(1-4C)alkoxycarbonylderivative thereof, for use in medicine.
 7. A method of treating adisease or medical condition mediated alone or in part by one or moreleukotrienes which comprises administering to a warm-blooded animalrequiring such treatment an effective amount of an indazolone of theformula I as claimed in any one of claims 1 to 3, or apharmaceutically-acceptable salt thereof, or 1-(1-4C)alkoxycarbonylderivative thereof.